Oxazolin-5-ones, formation

NMR studies at low temperature provided evidence for the formation of a mono-cationic oxazoline—zirconocene complex in which the substrate is a bidentate ligand and one triflate is still coordinated to the zirconium [4],... 

C, and then three molecular equivalents of acetyl chloride and triethy-lamine were added. Three types of acetylated materials, 11, 12, and 13, were isolated accompanied by a small amount of thioketone 7 and thioamide 9 (Scheme 8 and Table 6). All of the acetylated materials showed optical activity. For the reaction of 6a, 84% ee of 2-(acetylthio)aziridine 11a, 50% ee of 4-(acetyl-thio)oxazoline 12a, and 20% ee of 4-(acetylthio)oxazolidin-2-one 13a were obtained in 39,10, and 16% yields, respectively. In the reaction of 6b,c, the corresponding optically active materials 11-13 were obtained as shown in Table 9. The formation of oxazoline 12 involves the rearrangement ofAT-acyl aziridines, which occurs by intramolecular attack of the carbonyl oxygen at the ring carbon to cause rupture of the system. 

The reaction of ketoximes 235 with dimethyl carbonate in the presence of K2CO3, carried out in an autoclave at 180-190 °C, afforded 3-methyl-4,5-disubstituted 4-oxazolin-2-ones 236 (equation 102). The formation of compounds 236 occurred via [3,3]sigma-tropic rearrangement of intermediates of the oxime methylated with dimethyl carbonate. 

An unusual example of oxazoline formation is illustrated in the following example in which the hydroxyl moiety is masked as a tetrahydrofuran ring. Depending on reaction conditions, regioselective ring closure to one of the two oxazolines can be realized. Thus, addition of methanesulfonyl chloride to a mixture of substrate and EtsN resulted in the expected oxazoline 46. On the other hand, addition of < 1 equiv of triethylamine to a mixture of substrate and methanesulfonyl chloride, followed by acid catalysis produced oxazoline 47. Intermediate 47, obtained in 72% overall yield from 45, was susequently converted to the human immunodeficiency virus (HlV)-protease inhibitor Nelfinavir 48 (Scheme 8.18). 

Metal complexes of bis(oxazoline) ligands are excellent catalysts for the enantioselective Diels-Alder reaction of cyclopentadiene and 3-acryloyl-l,3-oxa-zolidin-2-one. This reaction was most commonly utilized for initial investigation of the catalytic system. The selectivity in this reaction can be twofold. Approach of the dienophile (in this case, 3-acryloyl-l,3-oxazolidin-2-one) can be from the endo or exo face and the orientation of the oxazolidinone ring can lead to formation of either enantiomer R or S) on each face. The ideal catalyst would offer control over both of these factors leading to reaction at exclusively one face (endo or exo) and yielding exclusively one enantiomer. Corey and co-workers first experimented with the use of bis(oxazoline)-metal complexes as catalysts in the Diels-Alder reaction between cyclopentadiene 68 and 3-acryloyl-l,3-oxazolidin-2-one 69 the results are summarized in Table 9.7 (Fig. 9.20). For this reaction, 10 mol% of various iron(III)-phe-box 6 complexes were utilized at a reaction temperature of —50 °C for 2-15 h. The yields of cycloadducts were 85%. The best selectivities were observed when iron(III) chloride was used as the metal source and the reaction was stirred at —50 °C for 15 h. Under these conditions the facial selectivity was determined to be 99 1 (endo/exo) with an endo ee of 84%. 

The initial stage of this scheme, i.e. the formation of the 2-allyl-3-oxazolin 5-one, proceeds via intermediacy of the 4-allyl-2-oxazolin-5-one (399) which is converted to (400) by a... 

Simple alkylation of the chiral chelate complex leads to formation of chiral dialkylacetic acids (Scheme 109).3S5 388 Simpler chiral enamines can also be used. The formation of chiral propanoic acids results from a resolution of racemic alkyl halides by the interaction of a chiral lithiooxazoline, which recognizes and reacts with one enantiomer at the expense of the other (Scheme 110).389 The above aspects of the asymmetric carbon—carbon bond formation from chiral oxazolines have been reviewed by Meyers.390... 

In contrast to the isoxazolones, the isomeric 4//-oxazolin-5-ones which lack the weak N—O bond usually lose only CO upon pyrolysis. Thus, FVP of a variety of compounds 354 at 600°C gives the acylketenimines 355167. The 2//-oxazolin-5-ones do lose CO2 to give iminocarbenes, which may undergo rearrangement, as in the formation of 357 from... 

The structurally novel antimitotic agent curacin A (1) was prepared with an overall yield of 2.5 % for the longest linear synthesis. Three of the four stereogenic centers were built up using asymmetric transformations one was derived from a chiral pool substrate. Key steps of the total synthesis are a hydrozirconation - transmetalation protocol, the stereoselective formation of the acyclic triene segment via enol triflate chemistry and another hydrozirconation followed by an isocyanide insertion. For the preparation of the heterocyclic moiety of curacin A (1) the oxazoline - thiazoline conversion provides efficient access to the sensitive marine natural product. 

One recent publication from the group of Abu-Omar reports on a condensation reaction involving glycerol and furfural, both renewables, to produce dioxolanes, formally a dehydration reaction. Here, a cationic oxorhenium(V) oxazoline species is used as the catalyst for the formation of various 1,3-dioxalanes from furfural with diols or epoxides under mild conditions (Scheme 21). Especially interesting is the reaction of furfural with glycerol to obtain a 70 30 mixture of the corresponding 1,3-dioxolane and 1,3-dioxane in solvent-free conditions [125]. 

The lack of reactivity of the aryloxazolinones (65) in photocycloaddition to many of the olefins other than 1,1-dimethoxyethene and furan probably results from efficient decay of E2 or D. Exciplex E2 and diradical D are proposed as intermediates in these cases for several reasons. Exciplex formation is most likely dependent on olefin ionization potential, and the ionization potential of many of the un-reactive olefins are intermediate between the ionization potential of furan and 1,1-dimethoxyethene as determined from the maxima of tetracynoethylene olefin charge transfer bands60 66,67. Although ds-2-butene does not form a cycloadduct with 2-phenyl-2-oxazolin-4-one (65a), ds-2-butene is isomerized to rram-2-butene during the irradiation52. Cis-trans isomerization is expected from decay of a triplet diradical. Decay of the exciplex and diradical intermediates in competition with reaction presumably results from steric hindrance from the aryl substituent. The olefins which give cycloadducts, furan and 1,1-dimethoxyethene, are expected to produce low steric hindrance with the aryl substituent in an exciplex or diradical. 

Hubert and co-workers have reported that alkyl diazoacetates react with A -diisopropylcarbodiimide in the presence of transition metal salts to give 2-isopropylimino-3-isopropyl-5-alkoxy-4-oxazolines.115 For example, treatment of ethyl diazoacetate with rhodium(II) acetate in the presence of A,A -diisopropylcarbodiimide (215) produced 2-iso-propylimino-3-isopropyl-5-ethoxy-4-oxazoline (217) in good yield. The formation of oxazoline 217 was interpreted in terms of an addition of ethoxycarbonylcarbene onto one of the nitrogen atoms of the carbodi-imide to give the transient ylide 216 which then cyclized to produce the observed heterocycle. 

There is one example, unique for several reasons, of the formation of a four-membered ring by anionic cyclisation onto an oxazoline. Attempted oxazoline-directed lithiation of the styrene 122 gave, instead, the cyclobutane 124 via addition of the alkyllithium to give a benzylic organolithium 123 which cyclises stereoselectively.63 The initial intermolecular carbolithiation proceeds remarkably easily - no additives (such as TMEDA) are required, even with MeLi. 

In aromatic systems, oxazolines can have three different functions (Fig. 4). Firstly, they can be used as protecting groups for carboxylic acids. Secondly, they activate even electron-rich aromatic systems for nucleophilic substitution. Fluorine or alkoxy groups in the ortho position can be substituted by strong nucleophiles such as Grignard reagents. Thirdly, when biaryl compounds with axial chirality are synthesized in these reactions, oxazolines can induce the formation of only one atropisomer with excellent selectivity. These three qualities were all used in the synthesis of 20, a precursor of the natural product isochizandrine [10]. 

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